Overcoming Resistance to MEK Inhibitor Treatment in Malignant Peripheral Nerve Sheath Tumor (MPNST)
Abstract
Miguel Miranda-Román, Principal Investigator of this proposal, is a committed and motivated Ph.D. cancer biology graduate student and researcher who wants to positively contribute by helping advance the knowledge of the cancer biology field for the generations to come. After attaining my Ph.D. degree at Memorial Sloan Kettering Cancer Center (MSKCC), a productive post-doctoral training will then help strengthen my planned candidacy for academic appointments as an independent investigator in the cancer biology field. It will be a great honor to be awarded the PRCRP Horizon Award and also a great opportunity for the advancement of my career as a scientist. The proposed research for this award is focused on the study of malignant peripheral nerve sheath tumor (MPNST), a disease that is known to affect the young adult population and that currently possesses limited treatment options. During the course of the proposed fellowship period, I will acquire extensive research experience by the daily research activities, the exposure to the diverse cancer research at MSKCC and my plan to attend and present research updates at different seminars and national cancer conferences. This, in addition with the mentoring of Dr. Chi, a physician-scientist and expert in the MPNST disease, will provide me with all the tools, knowledge, and experience necessary to achieve my career goals of becoming an independent scientist and mentor in an academic research institution. This research proposal is going to study different aspects of the MPNST disease. MPNST is a very aggressive type of sarcoma that originates from the cellular component of the peripheral nerves. This disease has very limited treatment options and can occur in the setting of neurofibromatosis type I (NF1-associated), sporadically or in association with previous radiotherapy treatment. Using comprehensive genomic approaches, we and others recently discovered that the majority of MPNSTs present an inactivation of the NF1 and Polycomb repressive complex 2 (PRC2) tumor suppressor pathways. Loss of NF1 results in a sustain activation of cell signaling pathways that promote tumor growth. Previous experiments assessed the feasibility of using MEK inhibitors as a way to block this signaling and negatively affect tumor growth. However, MPNST tumors are able to develop resistance to this single drug treatment. For this reason, this proposal is going to specifically study how these tumors develop this resistance and if the frequent loss of PRC2 function may have a role in affecting the sensitivity of this cells to the drug treatment. After understanding these aspects of MPNST, we will use this knowledge to identify and develop new combination treatment strategies that when used with MEK inhibitors (Trametinib), will overcome the ability of MPNST to develop drug treatment resistance. Based on the nature of this proposed research, results from this proposal will be able to have a direct positive impact on the clinic, as it will suggest a potential combination therapy for MPNST patients. The successful completion of this proposal will not only identify a better combination treatment strategy, but it also will provide the necessary pre-clinical results needed to support this treatment strategy as a novel combination therapy that could lead to decreasing the mortality for the thousands of MPNST patients. In addition to helping patient care, this research will also help further the advancement of the cancer research field since it will describe mechanisms through which cancer cells can become resistant to single drug treatment and will also describe how PRC2 loss may affect cancer sensitivity to targeted therapy. These last results will not be only relevant to this disease since other types of cancer also present loss of PRC2 function. In summary, the proposed research will be of great benefit to all the active and retired military members, their families and the general population, since its co
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910268
Entities
People
- Miguel Miranda-roman
Organizations
- Sloan-Kettering Institute
- United States Army